This application is a 371 of PCT/US92/01830 filed Mar. 4, 1992.
1. Field of the Invention
The present invention is generally related to neolignan derivatives which inhibit both platelet activating factor and 5-lipoxygenase for the treatment of inflammatory and allergic disorders.
2. Description of the Prior Art
Platelet activating factor (PAF) is a highly potent ether linked phospholipid (1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) which activates platelets as well as modulates the function of leukocytes and other target cells. PAF has been shown to be a mediator of a variety of pathophysiological conditions including arthritis, acute inflamation, asthma, endotoxic shock, pain, psoriasis, ophthalmic inflammation, ischemia, and gastrointestinal ulceration. Interaction with a specific membrane recognition site coupled to phosphatidylinositol metabolism produces the biological activity of PAF. Hence, blocking the PAF receptor can provide beneficial medical results in human beings and mammals suffering from diseases or disorders mediated by PAF.
Several PAF antagonists have recently been synthesized or isolated from natural sources. For example, Shen et al. in Proc. Natl. Acad. Sci. (U.S.A.), 82. 672-678 (1985), reported that kadsurenone, a neolignan derivative isolated from Piper fotukadsura Sieb et Zucc (a Chinese herbal plant), was a potent, specific and competitive inhibitor of PAF at the receptor level. Biftu et al., in J. Med. Chem. 29, 1917 (1986), and Ponpipom et al., in Biochem. Bioshys. Res. Comm. 150, 1213 (1988), have shown that 2,5-diaryltetrahydrofurans L-652,731 and L-659,989 (both of which are synthetic analogs of neolignan), respectively, are potent PAF receptor antagonists. U.S. Pat. No. 4,539,332 to Biftu et al. and U.S. Pat. No. 4,595,693 to Biftu et al. are both related to the use of 2,5-diaryltetrahydrofurans and their analogs as PAF antagonists. Graham et al., in 197th Amer. Chem. Soc. National Meeting Abstracts, 1989, MEDI, 25, 20, Corey, et al. in Tet. Lett., Vol. 29, 2899-2902 (1988), and U.S. Pat. No. 4,656,190 to Shen et al. respectively show that 1,3-diarylcyclopentanes, 2,4-diaryldioxolanes, and indene derivatives are also potent PAF receptor antagonists.
Leukotrienes, lke PAF, are potent lipid mediators of a variety of topical and systemic diseases and disorders. 5-lipoxygenase catalyzes the conversion of arachidonic acid to leukotriene A4 which is the precursor of leukotrienes B4 and C4. Leukotrienes B4 and C4 are oxygenated metabolites that contribute to the pathogenesis of such inflammatory disorders as arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are released concomitantly from leukocytes with PAF from a common phospholipid precursor upon cellular activation and act synergistically with PAF in many biological models. It has been demonstrated that a physical combination of a PAF antagonist and a leukotriene inhibitor is significantly more effective than either agent alone in treating asthma in an animal model (see, O'Donnell et al. in Therapeutic Approaches to inflammatory Diseases, Lewis et al., Elsevier, New York, 1989, pp.169-193).
Shen et al., in PAF and Related Lipid Mediators, Plenum Pub., New York, 164 (1987) and Page et al., in Trends in Pharmacol. Sci. 10, 1 (1989), pointed out that single compounds which posess the dual inhibitory capability of PAF and leukotriene inhibition would have greater antiinflammatory activities than a physical combination of a PAF and a leukotriene inhibitor. Moreover, the chemical combination of PAF and 5-lipoxygenase inhibitory activities in one molecule has advantages over drug combinations in terms of optimal pharmacokinetics, clinical applications and developmental costs. However, few compounds are known which posess this dual inhibitory activity. Shen et al., in PAF and Related Lipid Mediators, Plenum Pub: New York, 153-190 (1987), reported that a tetrahydrothiophene analog of lignan, L-653,150, is both a potent PAF antagonists and a moderate inhibitor of 5-lipoxygenase. European Pat. No. Application 0,365,089 to Biftu, filed Oct. 13, 1989, is also directed the use of tetrahydrothiophene analoqs as leukotriene inhibitors and specific PAF antagonists.
Because of the large number of diseases and disorders which are mediated by leukotrienes and PAF, synthesis of new compounds which posess leukotriene or PAF inhibitory activity, and preferably compounds which possess both inhibitory activities, as well as the identification of existing compounds which possess either or both inhibitory activities, will provide a great benefit to society in the treatment of those diseases and disorders.